Contact Dermatitis • Original Article COD

Contact Dermatitis

Methotrexate use in allergic contact dermatitis: a retrospective study

Ashaki Patel , Erin Burns and Nicole M. Burkemper
Departments of Dermatology and Pathology, Saint Louis University, St Louis, MO, 63104, USA

doi:10.1111/cod.12925

Summary Background. Methotrexate, a folate antimetabolite, is used to treat atopic dermatitis

and psoriasis. Although methotrexate’s therapeutic efficacy has been noted in the liter-
ature, there are few data on the efficacy of methotrexate treatment for allergic contact
dermatitis.
Objective. To evaluate the efficacy and tolerability of methotrexate in treating allergic
contact dermatitis at a single institution, and also to assess methotrexate efficacy in
patients with chronic, unavoidable allergen exposure.
Methods. We performed a retrospective chart review of 32 patients diagnosed with
allergic contact dermatitis by positive patch test reactions, and who received treat-
ment with methotrexate from November 2010 to November 2014. Demographic and
treatment-associated data were collected from electronic medical records. Ten patients
were identified as allergen non-avoiders secondary to their occupation, and were sub-
grouped as such.
Results. Seventy-eight per cent (25/32) of patients showed either a partial or a complete
response. Methotrexate had a comparable efficacy rate in the allergen non-avoiders
subset, at 10 of 10. Of the 32 patients, 23% (5/22) had complete clearance of their
dermatitis, and 1/10 of allergen non-avoiders had complete clearance of their dermatitis.
Conclusion. Methotrexate is a well-tolerated and effective treatment for allergic con-
tact dermatitis, and shows comparable efficacy to immunomodulatory agents such as
cyclosporine and azathioprine, with robust efficacy despite persistent allergen exposure
in patients with allergic contact dermatitis.

Key words: allergic contact dermatitis; contact dermatitis; drugs; methotrexate;

occupational.

Allergic contact dermatitis has many clinical presenta- chronic dermatitis or delayed wound healing. Although
tions. Often, it will present as pruritic, erythematous, allergic contact dermatitis is initially limited to the prin-
oedematous papules, vesicles and/or plaques at the site cipal site of exposure, it can spread to distant cutaneous
of allergen contact. At other times, it can present as sites (auto-eczematization) and can result in a more seri-
ous clinical presentation (1). Overall, allergic contact der-
matitis is a common, potentially chronic, disease with a
Correspondence: Dr Nicole M. Burkemper, Department of Dermatology, significant impact on quality of life. For some patients, the
1755 S. Grand Blvd, St Louis, MO 63104, USA. Tel: +1 314 2563435; Fax: culprit allergen(s) can be quickly identified by patch test-
+1 314 256 3431. ing, and removed from the patient’s environment. How-
Email: [email protected]
ever, often, the allergenic sources are either unidentifiable
or unavoidable – two situations that require symptomatic
Conflict of interests: The authors of this manuscript have no conflicts of and potentially immunosuppressive therapy to reduce the
interest, sources of funding, and/or other personal/financial relationships
effects of the disease.
requiring disclosure.
A variety of medications for use in the treatment
Accepted for publication 16 October 2017 of allergic contact dermatitis have been reported in

© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Contact Dermatitis 1
METHOTREXATE USE IN ALLERGIC CONTACT DERMATITIS • PATEL ET AL.

controlled trials, case series, and reviews (2–8). These The patients in this study were patch tested with the
medications fall under the categories of corticosteroids, North American Contact Dermatitis Group (NACDG)
non-steroidal drugs, immunomodulators, barrier creams, baseline series, which contained up to 65 allergens.
and emollients. In the category of immunomodulators, Many patients were tested with additional allergen
azathioprine and cyclosporine are described in the litera- series, depending on clinical suspicion. Testing was
ture as treatment options for allergic contact dermatitis performed with the Finn Chamber® system (Epitest,
(9–13). However, there are very few reports on the use Tuusula, Finland) on Scanpor® tape (Norgesplaster
of methotrexate in allergic contact dermatitis, and there Alpharma, Vennesla, Norway). Allergens were supplied
have been no controlled clinical trials on its use in this by Chemotechnique Diagnostics (Vellinge, Sweden).
setting. Handa et al. showed that methotrexate is as effi- Patches were applied to the patient’s back for 48 h before
cacious as azathioprine in the treatment of Parthenium removal. Readings were completed on day (D) 3 and D5
hysterophorus allergic contact dermatitis, but with a for all patients. The reactions were graded as doubtful,
shorter treatment time (6). Additionally, methotrexate +, ++, or +++, on the basis of the NACDG grading
may be useful in treating severe P. hysterophorus dermati- protocol (19).
tis that is unresponsive to conventional treatment (7, Data extracted included: sex, age, ethnicity, occu-
8). pation, rash distribution, previous treatment(s), disease
Methotrexate is a folate analogue antimetabolite that severity, concomitant diseases, rash initiation, methotrex-
is used in the treatment of a broad range of inflammatory ate start/stop dates, response to methotrexate, that
diseases. In dermatology, methotrexate has been proven is, efficacy, maximum dose of methotrexate achieved
to be effective in the treatment of psoriasis, atopic der- (g/week), tolerability of methotrexate taper, reason for
matitis, and other T cell-mediated skin diseases (14–16). discontinuation, name/number of allergens, methotrex-
Methotrexate is known to have several mechanisms of ate side-effects, and any concurrent treatments.
action. In psoriasis specifically, it targets proliferating
lymphoid cells and inhibits the migration of activated Results
T cells into certain tissue sites (17). Methotrexate also
has immunosuppressive effects by inhibiting DNA syn- The study included 32 patients at Saint Louis University
thesis in immunologically active cells, and suppressing who were diagnosed with allergic contact dermatitis via
primary and secondary antibody responses. Additionally, positive patch test reactions between November 2010
methotrexate increases adenosine production and thus and November 2014, and were subsequently treated for
has anti-inflammatory effects (18). allergic contact dermatitis with a once-weekly oral dose
The objective of this study was to evaluate the use of methotrexate for > 3 months. These patients’ charts
of methotrexate in the treatment of allergic contact der- were reviewed. Among the 32 patients, a subset of 10
matitis at a single institution. The aim was to better patients were identified as being exposed to ‘occupational
understand the efficacy and tolerability of methotrexate hazards/unavoidable allergens’. Patients in this subset
in patients with allergic contact dermatitis, and to deter- included those whose professions or hobbies introduced
mine the patient characteristics and disease-specific sce- constant unavoidable exposure to at least one relevant
narios in which methotrexate may be most effective. It is allergen. Some examples from the subset include hair-
of note that methotrexate is not currently Food and Drug dressers, welders, nurses, and photographers. Within
Administration-approved for use in allergic contact der- this category, 9 of 10 patients showed at least a partial
matitis. response to treatment with methotrexate; 1 of 10 tapered
off because of clearance of allergic contact dermatitis,
and 8 of 10 patients remained on methotrexate. All 10
Methods patients in this subset showed methotrexate efficacy,
Data for the study were obtained from a retrospective defined as either partial or complete efficacy.
chart review of patients diagnosed with allergic contact Among all other patients, 5 of 22 (23%) showed com-
dermatitis between November 2010 and November 2014 plete clearance and 10 of 22 (45%) showed a partial
in the Dermatology Department at Saint Louis University. response. The overall efficacy in this group was 15 of
Inclusion criteria included a diagnosis of allergic contact 22 (68%). Table 1 shows the total number of positive
dermatitis via positive patch test reactions, and treatment allergens tested in each patient, along with important
with methotrexate for > 3 months. A total of 770 patient methotrexate treatment parameters in both subsets of
charts were extracted, of which 37 matched the inclusion patients.
criteria. Of the 37 charts, 5 were excluded because of Overall, of the 32 patients treated with methotrexate,
insufficient data. only 2 discontinued methotrexate use completely, owing

© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
2 Contact Dermatitis
 METHOTREXATE USE IN ALLERGIC CONTACT DERMATITIS • PATEL ET AL.

Table 1. Allergen and methotrexate treatment data by patient subset

No. of positive Maximum dose of Methotrexate Methotrexate

Number allergens/total allergens methotrexate achieved (g/week) duration (days) response

Occupational hazards/allergen non-avoiders[1]

1 20/100 20 1017 Yes, clear
2 5/107 22.5 706 Yes, partial
3 5/106 22.5 330 Yes, partial
4 18/118 25 395 Yes, partial
5 16/107 15 790 Yes, partial
6 29 799 25 500 Yes, partial
7 39/107 20 224 Yes, partial
8 6/118 15 282 Yes, partial
9 23 802 22.5 Unknown Yes, partial
10 22/88 25 528 Yes, partial
All other patients[2]
1 24 047 20 141 Yes, clear
2 24 746 15 731 Yes, clear
3 23 863 20 363 Yes, clear
4 32/143 25 311 Yes, clear
5 6/114 15 Unknown Yes, clear
6 9/114 25 895 Yes, partial
7 6/122 20 462 Yes, partial
8 21/133 20 Unknown Yes, partial
9 23/67 15 517 Yes, partial
10 32 264 20 224 Yes, partial
11 3/106 15 136 Yes, partial
12 8/107 15 107 Yes, partial
13 9/107 15 96 Yes, partial
14 35 490 30 1214 Yes, partial
15 2/65 + 5/114* 25 529 Yes, partial
16 8/114 25 350 No
17 15/106 25 602 No
18 10/121 25 113 No
19 14/65 25 348 No
20 15/108 30 165 No
21 3/107 25 1620 No
22 5/100 22.5 Unknown No
∗ Patient was patch tested twice on two different dates.
[1] Patients with professions/hobbies forcing constant, unavoidable exposure to at least one relevant allergen.
[2] Patients who didn’t have an occupational exposure and had the ability to avoid their allergen.

to fatigue and pulmonary infection. The remaining 30 Discussion

of 32 patients (94%) found it tolerable and continued This retrospective analysis of patients at a single institu-
treatment. Altogether, 78% of patients (25/32) showed tion shows the potential of methotrexate for the treat-
methotrexate efficacy, and 22% (7/32) showed failure, ment of recalcitrant allergic contact dermatitis. Of the 32
including the 2 patients who discontinued use because of patients treated with methotrexate, 78% (25/32) showed
intolerable side-effects (Fig. 1). clinical improvement and 22% (7/32) failed to respond.
The most common side-effects noted among all of the Of the 25 responders, 6 of 25 (24%) were noted to have
32 patients were gastrointestinal discomfort (21%) and complete clearance of allergic contact dermatitis, and
fatigue (16%). Laboratory abnormalities included ALT 19 of 25 (76%) were reported to have partial clearance.
over 56 U/L and/or AST over 40 U/L (31%), anaemia The 22% of non-responders included those patients who
(15%), elevated creatinine (8%), leukopenia (6%), and stopped using methotrexate because the medication sim-
thrombocytopenia (3%). It is of note that all documented ply showed no benefit, or caused an intolerable side-effect.
laboratory abnormalities were mild, were transient, and Azathioprine and cyclosporine have long been used as
resolved without dose adjustments. pharmacotherapies in the treatment of allergic contact

© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
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METHOTREXATE USE IN ALLERGIC CONTACT DERMATITIS • PATEL ET AL.

12 of treatment in 42 adults with severe atopic dermati-

tis; however, patients on azathioprine experienced more
adverse events, including gastrointestinal events, abnor-
malities in blood counts, and increased liver enzymes
(15). Similarly, Garritsen et al. showed that azathioprine
was more likely than methotrexate to cause influenza-like
symptoms, pancytopenia, and liver dysfunction (24).
Cyclosporine has shown efficacy in chronic hand eczema,
but has also led to exacerbations of allergic contact der-
matitis (25–27). Another study examining drug survival,
that is, the length of time that a patient is on a particular
medication, which is a well-recognized measure of drug
effectiveness, in patients treated with cyclosporine for
atopic dermatitis showed a drug survival rate of only 18%
after 2 years, and cited side-effects and ineffectiveness
as the two main reasons for decreased drug survival
Fig. 1. Of the 32 patients treated with methotrexate for allergic (28). The predominant side-effects leading to discon-
contact dermatitis, 78% (25/32) showed a clinical response, with tinuation of cyclosporine treatment were hypertension,
59% (19/32) showing partial clearance and 19% (6/32) showing gastrointestinal symptoms, headache, and an increase in
full clearance of their allergic contact dermatitis. Twenty-two per
cent (7/32) had treatment failure or were not able to tolerate
serum creatinine (28). Our study shows that methotrex-
methotrexate treatment. ate has similar efficacy to both azathioprine and
cyclosporine in the treatment of allergic contact dermati-
tis, but with less potential for significant side-effects or
dermatitis (9). Some studies have established the efficacy adverse events.
of azathioprine for the treatment of allergic contact der- Additionally, this study has shown the potential use of
matitis caused by P. hysterophorus (10–13). However, methotrexate as a treatment method for allergic contact
a systematic review of azathioprine use in dermatology dermatitis in a special subset of patients, that is, ‘occupa-
showed that there is a strong clinical recommendation for tional allergen/unavoidable allergen’, which accounted
the use of azathioprine in atopic dermatitis, whereas only for 31% of all patients reviewed. Within this subset
moderate-quality data exist for its use in off-label settings alone, 9 of 10 patients showed at least partial effective-
such as allergic contact dermatitis (20). Moreover, a ran- ness of methotrexate; 1 of these patients had complete
domized trial conducted on patients suffering from aller- clearance of the dermatitis, and 2 stopped treatment
gic contact dermatitis caused by P. hysterophorus weed because of significant improvement. The remaining 7
comparing azathioprine with methotrexate showed that remain on methotrexate treatment and continue to show
methotrexate had similar efficacy as azathioprine, with improvement. All patients in this subset had a longer
a shorter treatment time being needed to achieve clear- duration of treatment than the average among the 32
ance. In the group treated with azathioprine, the clinical patients (530 days versus 470 days). This may suggest
severity score (CSS) was reduced by > 75% in 9.5 weeks, that long-term consistent treatment with methotrex-
whereas the group treated with methotrexate achieved ate may be needed to control disease, rather than that
a > 75% reduction in CSS in 5.6 weeks. Fifty per cent of methotrexate induces long-lasting remission.
the improvement in the methotrexate group was seen in The conclusions that can be drawn from this study are
the first month, and there was a sustained decrease in limited in the following ways. First, the number of cases
the dermatitis score with continuation for 6 months (6). reviewed is small, and specific to a demographic area.
Another study showed that methotrexate, both alone and Therefore, these data cannot be easily generalized. The
in combination with a topical corticosteroid, is a useful retrospective nature of this study means that it cannot
option in severe P. hysterophorus dermatitis that is unre- fully evaluate the full potential of methotrexate as a
sponsive to conventional treatment (7, 8). Methotrexate treatment method in various subsets of allergic contact
has also shown better efficacy than azathioprine in the dermatitis. Moreover, owing to the retrospective nature
treatment of atopic dermatitis in multiple studies (21, 22). of this study, there was no standardized definition of
Schram et al. showed similar reductions in the Severity partial or complete response, and usual methodological
Scoring of Atopic Dermatitis Score (SCORAD) (23) (42% requirements, such as the collection of body surface area
with methotrexate and 39% with azathioprine) at week and quality of life index, could not be met. Suggestions

© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
4 Contact Dermatitis
 METHOTREXATE USE IN ALLERGIC CONTACT DERMATITIS • PATEL ET AL.

for further studies include prospectively evaluating the Although various medications have been used thus far,
efficacy of methotrexate in a larger group of patients with methotrexate shows robust efficacy in the treatment of
chronic allergen exposure. patients with persistent allergen exposure, as shown in a
In conclusion, allergic contact dermatitis is a com- group of patients treated for allergic contact dermatitis at
a single institution.
mon disease that affects a wide range of patient subsets.

References
1 Gehrig K A, Warshaw E M. Allergic controlled study. Indian J Dermatol Venereol 21 Védie A, Ezzedine K, Amazan E et al.
contact dermatitis to topical antibiotics: Leprol 2008: 74: 453–454. Long-term use of systemic treatments for
epidemiology, responsible allergens, 12 Verma K K, Bansal A, Setharaman G. moderate-to-severe atopic dermatitis in
and management. JAAD 2008: 58: Parthenium dermatitis treated with adults: a monocentric retrospective study.
1–21. azathioprine weekly pulse doses. Indian J Acta Derm Venerol 2014: 96: 802–806.
2 Saary J, Qureshi R, Palda V et al. A Dermatol Venereol Leprol 2006: 72: 22 Schram M E, Roekevisch E, Leeflang M M
systematic review of contact dermatitis 24–27.
G et al. A randomized trial of
treatment and prevention. JAAD 2008: 13 Verma K K, Manchanda Y, Pasricha J S.
methotrexate versus azathioprine for
53: 845–855. Azathioprine as a corticosteroid sparing
severe atopic eczema. J Allergy Clin
3 Pigatto T D, Bigardi A S, Legori A et al. Are agent for the treatment of dermatitis
barrier creams of any use in contact Immunol 2011: 128: 353–359.
caused by the weed parthenium. Acta
dermatitis? Contact Dermatitis 1992: 26: Derm Venereol 2000: 80: 31–32. 23 Oranje A P. Practical issues on
197–198. 14 Heydendael V M, Spuls P I, Opmeer B C interpretation of scoring atopic dermatitis:
4 Tan C, Rasool S, Johnston G. Contact et al. Methotrexate versus cyclosporine in SCORAD index, objective SCORAD,
dermatitis: allergic and irritant. Clin moderate-to-severe chronic plaque patient-oriented SCORAD and three-item
Dermatol 2014: 32: 116–124. psoriasis. N Engl J Med 2003: 349: severity score. Pathogenesis and
5 Jacob S E, Castanedo-Tardan M P. 658–665. management of atopic dermatitis. Curr
Pharmacotherapy for allergic contact 15 Cooper K D. New therapeutic approaches Probl Dermatol 2011: 41: 149–155.
dermatitis. Expert Opin Pharmacother in atopic dermatitis. Clin Rev Allergy 1993: 24 Garritsen F, Roekevisch E, Schaft J V D
2007: 8: 2757–2774. 11: 543–559. et al. Ten years experience with oral
6 Handa S, De D, Sarangal R. The 16 Shaffrali F C G, Colber G B, Messenger A G immunosuppressive treatment in adult
comparative efficacy and safety of et al. Experience with low-dose
patients with atopic dermatitis in two
azathioprine vs. methotrexate as methotrexate for the treatment of eczema
academic centres. J Eur Acad Dermatol
steroid-sparing agent in the treatment of in the elderly. JAAD 2003: 48: 417–419.
Venereol 2015: 29: 1905–1912.
airborne-contact dermatitis due to 17 Jeffes E W, Mccullough J L, Pittelkow M R
Parthenium. Indian J Dermatol Venereol 25 Grandlun H, Erkko P, Reitamo S.
et al. Methotrexate therapy of psoriasis:
Leprol 2013: 79: 240–241. differential sensitivity of proliferating Long-term follow up of eczema patients
7 Kuchabal S D, Kuchabal D S. Contact lymphoid and epithelial cells to the treated with cyclosporine. Acta Derm
dermatitis to parthenium weed treated cytotoxic and growth-inhibitory effects of Venereol 1998: 78: 39–40.
with methotrexate and triamcinolone methotrexate. J Invest Dermatol 1995: 26 Grandlun H, Erkko P, Eriksson E et al.
acetonide. BMJ Case Rep 2011: 2011: 104: 183–188. Comparison of cyclosporine and topical
329–331. 18 Cronstein B N, Naime D, Ostad E. The betamethasone-17,21-diproprionate in
8 Sharma V K, Bhat R, Sethuraman G, antiinflammatory mechanism of the treatment of severe chronic hand
Manchanda Y. Treatment of Parthenium methotrexate. Increased adenosine release eczema. Acta Derm Venereol 1996: 76:
dermatitis with methotrexate. Contact at inflamed sites diminishes leukocyte 371–376.
Dermatitis 2007: 57: 118–119. accumulation in an in vivo model of 27 Prignano F, Bonciolini V, Bonciani D et al.
9 Alexandroff A B, Johnston G A. Medical inflammation. J Clin Invest 1993: 92: Exacerbation of allergic contact dermatitis
management of contact dermatitis. G Ital 2675–2682.
during immunosuppression with
Dermatol Venereol 2009: 144: 537–540. 19 Spring S, Pratt M, Chaplin A. Contact
cyclosporine A. G Ital Dermatol Venereol
10 Sharma V K, Chakrabarti A, Mahajan V. dermatitis to topical medicaments: a
2010: 145: 543–546.
Azathioprine in the treatment of retrospective chart review from the
parthenium dermatitis. Int J Dermatol Ottawa Hospital Patch Test Clinic. 28 Schaft J V D, Politiek K, Reek J V D et al.
1998: 37: 299–300. Dermatitis 2012: 23: 210–213. Drug survival for ciclosporin A in a
11 Verma K, Mahesh R et al. Azathioprine 20 Schram M E. Off-label use of azathioprine long-term daily practice cohort of adult
versus betamethasone for the treatment of in dermatology. Arch Dermatol 2011: patients with atopic dermatitis. Br J
parthenium dermatitis: A randomized 147: 474–475. Dermatol 2015: 172: 1621–1627.

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